Cancer is a fatal disease as a major cause of adult death, and the frequency of cancer is increasing. Most of the traditional drugs used for treating cancers, e.g., taxanes such as paclitaxel and doxetaxel; vinca alkaloids such as vincristine, vinblastine and vinorelbin; anthracyclines such as daunomycin and doxorubicin; camptothecins such as topotecan, irinotecan; actinomycin; and etopocid, are based on selective cytotoxicity, but such selectivity against cancer cells has been low thereby causing many side effects such as cytotoxicity to normal cells. Further, there are various problems that it is required for a patient to be hospitalized before his treatment, or the patient has to endure side effects such as those caused by excipients. Moreover, cancer cells frequently exhibit a resistance against an anticancer agent containing the above drugs.
To overcome such problems, many novel molecular-level targets have been identified by human genome sequencing, and they become available for treatment. Therefore, many studies are ongoing to develop an anticancer agent acting on specific targets in the cell not a cell itself, and to maximize the therapeutic effect of the anticancer agent without causing adverse side effects.
In cells, there are many signal transduction systems, which are functionally linked to each other to control the proliferation, growth, metastasis and death of cells. Protein tyrosine kinases play important roles in such cellular regulation, and their abnormal expression or mutation has been commonly observed in cancer cells. Protein tyrosine kinase is an enzyme which catalyzes the transportation of phosphate groups from ATP to tyrosines located on a protein substrate. Many growth factor receptor proteins function as tyrosine kinases to transport cellular signals. The interaction between growth factors and their receptors is necessary to control the normal cell growth, but abnormal signal transduction caused by the mutation or overexpression of any of the receptors may induce various diseases.
Further, protein tyrosine kinase receptors play important roles in a biochemical signal transduction passing through a cytoplasmic membrane. Transmembrane receptor molecules typically contain an inner cellular tyrosine kinase domain and an outer cellular ligand binding domain. The ligand binding of a receptor stimulates the phosphorylation of a tyrosine residue between the receptor and other inner cellular molecules, and the phosphorylation of the tyrosine residue induces signal transduction through various cellular reactions.
The comparison of homology of amino acid sequence discovers 19 subgroups of RTK (receptor tyrosine kinase) such as Flt (Fms-Like Tyrosine Kinase Receptor, Flt1 or VEGFR1), KDR (Kinase Insert Domain Containing Receptor, Flk-1 or VEGFR2), Flk4 (Fms-Like Tyrosine Kinase Receptor or VEGFR3), EGFR1 (Epidermal Growth Factor Receptor 1, Erb-B1 or HER-1), EGFR2 (Erb-B2 or HER-2), Erb-B3 and Erb-B4. Among theses, Flt and KDR are closely related to a vascular endothelial growth factor (VEGF) (see [De Vries et al., Science 255: 989-991, 1992; and Terman et al., Biochem. Biophys. Res. Comm. 187: 1579-1586, 1992]).
Protein tyrosine kinases have been classified into many families in terms of growth factors, and, specifically, VEGF-related VEGF receptor (VEGFR) tyrosine kinase has been intensely studied. The VEGFR tyrosine kinase is composed of a receptor and a tyrosine kinase, and delivers extracellular signals into the cell through the cellular membrane. The VEGFR tyrosine kinases are classified into VEGFR1, VEGFR2 and VEGFR3, and VEGFR2 (KDR) is a major VEGFR related to angiogenesis.
Unwanted pathological angiogenesis is related to diseases such as streaks of diabetes patient, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma and angioma, (see [Fan et al., Trends Pharmacol. Sci. 16: 57-66, 1995; and Folkman, Nature Medicine 1: 27-31, 1995]). The change caused by metastasis of blood vessel accompanies biological reactions in both normal and abnormal cases (see [Cullinan-Bove et al., Endocrinology 133: 829-837, 1993; and Senger et al., Cancer and Metastasis Reviews 12: 303-324, 1993]), and polypeptides stimulating epithelial cell growth in vitro include Fibroblast Growth Factor (aFGF and bFGF) and VEGF. In contrast to FGFs, VEGFs are active only in specific epithelial cells due to the limited expression of their receptor.
Recently, it is reported that VEGF acts as an important stimulator to normal and pathological angiogenesis (see [Jakeman et al., Endocrinology 133: 848-859, 1993; and Kolch et al., Breast Cancer Research and Treatment 36: 139-155, 1995]) and metastasis of a blood vessel (see [Connolly et al., J. Biol. Chem. 264: 20017-20024, 1989]), antagonism of VEGF induced by removing of the VEGF by using antibodies can inhibit the proliferation of cancer cells (see [Kim et al., Nature 362: 841-844, 1993]).
International Patent Publications WO 2000/59509, WO 2002/90346 and WO 1998/35958 each discloses PTK787 (Novartis), which comprises a phthalazine framework, and selectively inhibits tyrosine receptors such as VEGFR1, VEGFR2 and VEGFR3.
International Patent Publications WO 2001/45689, WO 2001/37820, WO 2001/60814, WO 1999/61422 and WO 1998/50356 each discloses SU11248 (Sutent, Pfizer), which comprises an indolidone framework, and inhibits tyrosine receptors such as VEGFR1, VEGFR2, VEGFR3 and PDGFR.
International Patent Publications WO 2001/32651, WO 2004/14383 and WO 2004/14426, and U.S. Pat. No. 3,039,551 each discloses ZD6474 (Zactima, AstraZeneca), which comprises a quinazoline framework, and inhibits tyrosine receptors such as VEGFR2 and EGFR1.
International Patent Publications WO 2000/47212, WO 2001/74360, WO 2002/12228, WO 2002/12227, WO 2000/21955 and WO 2000/47212 each discloses AZD2171 (AstraZeneca), which comprises a quinazoline framework, and selectively inhibits a tyrosine receptor, VEGFR2.
International Patent Publications WO 2001/10859, WO 2001/23375, WO 2003/68223, WO 2003/68228 and WO 2003/68229 each discloses Bay-439006 (sorafenib, Bayer), which comprises an urea framework, and inhibits tyrosine kinase receptors such as VEGFR2, VEGFR3 and Raf-1.
International Patent Publications WO 1997/2266, WO 1997/27199, WO 1998/7726 and WO 2003/13541 each discloses AEE788 (Novartis), which comprises a pyrrolopyrimidine framework, and inhibits tyrosine kinase receptors such as HER-1 (EGFR1), HER-2 and VEGFR2.
International Patent Publications WO 02059110 discloses Pazopanib (GlaxoSmithKline), which comprises a pyrimidine framework, and inhibits tyrosine kinase receptors such as PDGF, c-Kit, VEGFR1, VEGFR2 and VEGFR3.
Further, as another protein tyrosine kinase growth factor, EGF-related EGF receptor (EGFR) tyrosine kinase also has been intensely studied. A EGFR tyrosine kinase is composed of a receptor and a tyrosine kinase, and delivers extracellular signals to the cell nuclear through the cellular membrane. The EGFR tyrosine kinases are classified by their structural differences into EGFR1 (Erb-B1 or HER-1), Erb-B2 (HER-2), Erb-B3 and Erb-B4, and all of the above members can form a homodimer- or heterodimer-signal delivery complex. This shows that overexpression of more than one members in a malignant disease can induce synergistic modification. These overexpressions of more than one members are often observed in human malignant tumor.
Therefore, the inhibition of mutated or overexpressed EGFR tyrosine kinases has been considered to be useful for treating tumors, and many drugs have been developed therefor, e.g., Gefitinib, Erlotinib, Carnertinib, Lapatinib. These are low molecular compounds, and inhibit the growth of tumor by inhibiting the role of EGFR tyrosine kinase to prolong the life time of patients or to provide therapeutic advantages.
International Patent Publications WO 1996/33981, WO 1996/33979, WO 1997/38994 and WO 1996/33980 each discloses a quinazoline derivative substituted with an alkoxyalkylamino or alkylaminoalkoxy group; International Patent Publications WO 1997/30034 and WO 1996/16960 each discloses a quinazoline derivative substituted with aryl or heteroaryl group; and International Patent Publications WO 2003/40109 and WO 2003/40108 each discloses compounds having various aminoalkoxy substituents at position 5 of quinazoline (the quinazoline is named in accordance with a reference [J. A. Joule, Chapman & Hall, Heterocyclic chemistry, 3rd Ed., 189]).
International Patent Publication WO 1995/19970 and U.S. Pat. Nos. 5,654,307 and 5,679,683 each discloses various tricyclic heteroaryl compound. International Patent Publications WO 1999/6396, WO 1999/6378, WO 1997/38983 and WO 2000/31048 each discloses quinazoline compounds that inhibit the tyrosine kinase irreversibly. Further, European Patent 0787722, and WO 1998/50038, WO 1999/24037 and WO 2000/6555 each also discloses quinazoline compounds that inhibit the tyrosine kinase irreversibly; U.S. Pat. No. 6,225,318, European Patents 0387063 and 01292591, and International Patent Publications WO 2001/98277, WO 2003/45939 and WO 2003/49740 each discloses compounds having various alkenyl or alkynyl substituents at position 6 of quinazoline; and International Patent Publications WO 1998/43960, WO 2000/18761, WO 2001/47892, WO 2001/72711, WO 2003/50090, WO 1999/9016, WO 2000/18740 and WO 2000/66583 each discloses 3-cyanoquinoline compounds.
International Patent Publications WO 1998/2434, WO 1998/2437, WO 1999/35132, WO 1999/35146, WO 2001/4111 and WO 2002/2552 each discloses various quinazoline compounds substituted with furan having various sulfonealkylamino substituents; and International Patent Publications WO 2003/53466 and WO 2001/94353 each discloses thienopyrimidine compounds. Further, International Patent Publications WO 2001/12227, WO 2004/14386, WO 2004/35057 and WO 2001/76586 disclose various methods for effectively treating tumors in combination with drugs having different mechanism with the tyrosine kinase or radiation therapy.
However, the above mentioned conventional quinazoline derivatives have to be taken in large dose for intended treatments, which causes such side effects such as diarrhea and skin eruption. Accordingly, there has continued to exist a need to develop an effective drug in a small dosage that gives no adverse side effect.